AMPHOTERIC SURFACTANT FOR THE TREATMENT OF APHTHOUS ULCERS

Abstract: The present invention relates to the use of an amphoteric surfactant in the manufacture of a composition for the prevention, inhibition and/or reduction of aphthous ulcers. Preferably, the compositions are oral compositions such as toothpastes and mouthwashes. The oral composition is especially preferably in a gel form. Preferably the amphoteric surfactant is a betaine, particularly a fatty acidamidoalkylbetaine.

Description: Amphoteric surfactant for the treatment of aphthous ulcers. The present invention relates to the prevention, inhibition and/or reduction of minor recurrent aphthous stomatitis by the use of an oral composition which comprises an amphoteric surfactant. Aphthous stomatitis is a general term describing a disease affecting the mucous membrane in the mouth, causing the formation of small, whitish ulcers, called aphthae or more commonly aphthous ulcers. These aphthous ulcers cause severe discomfort to the patient as they are rather painful and irritating. Several treatments for aphthous ulcers have already been proposed, e.g. gargle compositions with an astringent material or with cellulosealkylethers or with homocarnosine, but none of these treatments have found wide usage as effective anti- aphthae treatments. We have now found that amphoteric surfactants have a considerable anti- aphthae activity, significantly preventing, inhibiting and/or reducing the formation of aphthous ulcers in the mouth. Consequently, the present invention relates to the use of an amphoteric surfactant in the manufacture of an oral composition for preventing, inhibiting and/or reducing aphthous ulcers. Amphoteric surfactants are well-known per se. They are surfactants of which the hydrophilic group has both acid and alkaline properties, depending upon the pH of the medium in which they are present. In acid media they form cations, and in alkaline media anions. In the isoelectric pH range they are present in the form of zwitterions. It is preferred in the present invention that the amphoteric surfactant is present in a cationic or zwitterionic form in the oral composition. Amphoteric surfactants have been described extensively in the prior art, and reference is made to Schwartz, Perry and Berch, Synthetic Detergents and Surfactants, Vol. I and II for further details which are hereby incorporated by way of reference. Typical examples can be represented by the following general formula: R,(R,) (R 3 )N*-R 4 -Y*, in which R, is a fatty alkyl or acyl residue, which may be interrupted by heteroatoms, R 2 and R 3 are hydrogen or short alkyl residues, R contains one or more methylene units and Y is an acid residue. Many varieties exist, and the aforementioned reference contains numerous examples of amphoteric surfactants. Typical examples are the alkylglycinates, alkylproprionates, betaines, sulphobetaines, phosphatobetaines, as well as tertiary amine oxides which, although not amphoteric in structure, behave like amphoteric surfactants. Specific examples are: sodium cocoamphoacetate disodium cocoamphodiacetate sodium carboxy ethyl oleic polypropylamine sodium cocoamphoproprionate disodium cocoamphodiproprionate lauryl betaine cocamidopropyl betaine tallow dihydroxyethyl betaine coco sultaine coca idopropyl hydroxysultaine lauryl dimethyl amine oxide n-alkyl ethoxy dimethyl amine oxide Particularly preferred are the fatty acidamidoalkyl betaines such as l-alcoylamino-3-dimethylammonio-propane- 3-carboxy methyl betaine, in which the alcoyl group contains from 7-17 carbon atoms. This product is commercially available from Th. Goldschmidt AG, Germany under the name Tego® Betain BL 281. The amphoteric surfactant is used in the present invention in an amount of 0.01-6%, usually 0.1-3% and preferably 0.25-2% by weight. The amphoteric surfactant-containing composition of the present invention can be manufactured in any form, suitable for orally administering the composition to achieve the prevention, inhibition and/or reduction of aphthous ulcers. Such forms are tablets, capsules, pills, powders, granules, solutions, gargles, suspensions, salves, gels, pastes etc. Preferably, the composiion is an oral composition. Particularly suitable forms of the oral composition are toothpastes, mouthwashes, gels and the like. Also it is possible to formulate the oral composition in forms, suitable for buccal administration, such as irrigator fluids, chewing gum, lozenges, and adhesive strips. Oral compositions in gel form are particularly preferred in the present invention. The oral composition may furthermore comprise conventional ingredients, such as pharmaceutically acceptable carriers like starch, sucrose, polyols, surfactants, water or water/alcohol systems etc. When formulated into a dentifrice, such formulation may contain all the usual dentifrice ingredients. Thus, they may comprise particulate abrasive materials such as silicas, aluminas, calcium carbonates, dicalciumphosphates, hydroxyapatites, trimetaphosphates, insoluble hexa etaphosphates and so on, usually in amounts between 5 and 60% by weight. Furthermore, the dentifrice formulations may comprise humectants such as glycerol, sorbitol, propyleneglycol, lactitol and so on. Minor amounts of additional surface-active agents may also be included such as anionic, nonionic and zwitterionic synthetic detergents. Examples thereof are sodiumlaurylsulphate, sodium dodecylbenzenesulphonate, sodium mono- and dioctyl-phosphate, sodiumlauroylsarcosinate, alkyleneoxide condensation products with fatty alcohols, with fatty acid esters, block copoly ers of ethylene oxide and propyleneoxide. Nonionic surface-active agents are preferred as additional surfactant when an additional surfactant is included. Binders and thickeners such as sodium carboxymethyl- cellulose, xanthan gum, gum arabic etc. may also be included, as well as synthetic polymers such as polyacrylates and carboxyvinyl polymers such as Carbopol®. Flavours such as peppermint and spearmint oils may also be included, as well as preservatives, opacifying agents, colouring agents, pH-adjusting agents, sweetening agents and so on. Anti-bacterial agents may also be included such as chlorhexidine, copper-, zinc- and stannous salts such as zinc citrate and stannous pyrophosphate, sanguinarine extract, metronidazole. Further examples of anti-bacterial agents are quaternary ammonium compounds such as cetylpyridinium chloride; bis-guanides such as chlorhexidine digluconate, hexetidine, octenidine, alexidine; halogenated bisphenolic compounds such as 2,2' methylenebis-(4-chloro-6-bromophenol) . A preferred anti- bacterial agent is Triclosan (2 1 ,4 ,4 * -trichloro-2-hydroxy- diphenylether) . The amount of Triclosan used in the present invention may vary from 0.0001 - 5% by weight, preferably from 0.01 - 3% by weight and particularly preferably from 0.1 - 2% by weight of the oral composition. Polymeric compounds which can enhance the delivery of active ingredients such as the anti-bacterial agents can also be included. Examples of such polymers are copolymers of polyvinylmethylether with maleic anhydride and other similar delivery enhancing polymers, e.g. those described in DE-A-3,942,643 (Colgate) Furthermore anti-inflammatory agents such as ibuprofen, flurbiprofen, aspirin, indo ethacin etc. may also be included. Anti-caries agents such as sodium- and stannous fluoride, aminefluorides, monosodiumfluorophosphate, calcium lactate and/or calcium glycerophosphates, strontium salts and strontium polyacrylates, casein and casein digests and phosphoproteins may also be included. Other optional ingredients include vitamins such as Vitamin C, plant extracts, potassium salts such as potassium citrate, potassium chloride and potassium nitrate. Other optional ingredients include enzymes such as dextranase and/or mutanase, amyloglucosidase, glucose- oxidaεe with lactoperoxidase, neuraminidases, and hydrogenperoxide generating compounds such as potassiu peroxydiphosphate. Furthermore, the oral compositions may comprise anti- calculus agents such as alkalimetalpyrophosphates, hypophosphite-containing polymers, organic phosphonates, phosphocitrates etc.. Other optional ingredients that may be included are e.g. bacteriocins, bacteriophages, tissue respiratory factors, antibodies, bleaching agents such as peroxy compounds, effervescing systems such as sodiumbicarbonate/citric acid systems, colour change systems, and so on. Preferred amphoteric surfactant-containing compositions for use in the present invention contain Triclosan, either alone or together with a zinc salt such as zinc citrate. The amount of zinc salt used in such combination ranges from 0.01 - 5% by weight of the composition, preferably from 0.1 - 3% by weight of the composition. Other suitable zinc salts are those, disclosed in US-A-4, 022 ,880, as well as alkalimetal zinc citrates such as sodium zinc citrate. Also preferred for use in the present invention are amphoteric surfactant-containing compositions which contain Triclosan and a copolymer of polyvinylmethylether with maleic anhydride or another delivery-enhancing polymer as described in DE-A-3 ,942 , 643. The amount of such polymer may vary from 0.005-4% by weight of the composition. A zinc salt may also be present in these polymer-containing compositions, such as zinc citrate or zinc glycinate in the above specified amounts. The invention will further be illustrated by the following Examples: Example 1 The following toothpaste formulations were tested as to their effect on the incidence of aphthous ulcers: wt % Sorbitol, 70 % syrup 45.00 Abrasive silica 10.00 Thickening silica 10.00 Xanthan gum 1.00 Saccharin 0.20 Titanium dioxide 1.00 Sodium monofluorophosphate 0.80 Flavour 1.00 Polyethylene glycol 5.00 Surfactant X Water q.s The compositions contained either no surfactant at all (A) , or 1.9 % cocamidoprop ' yl betaine (B) or 1.5 % sodium laurylsulphate (C) . Patients suffering from recurrent aphthous ulceration were treated with the formulations using the following method: patients brushed with the test and placebo formulations for identical periods of time, and the numbers of new ulcers formed over each period were compared. Products were tested sequentially, with each patient using each product during the test. The test involved 25 patients, and the following results were obtained: Toothpaste A B C Mean number 7.36 ± 1.3 9.16 ± 1.2 13.12 ± 1.7 of ulcers ± SEM Example 2 The effect on abnormal desquamation (or sloughing) of the toothpastes with varying amounts of cocamidopropyl betain (CAPB) (B) or sodium laurylsulphate (SLS) (C) was determined, in a study involving 28 patients using a cap- splint. A custom-made cap-splint containing the test toothpaste was placed over the attached gingiva lining the upper dentition (2 min./appln., bid, 4 days) . The affected gingiva was then examined for any sloughing caused by the toothpaste treatment. The following results were obtained: Toothpaste B 0.64 % CAPB 1.27 % CAPB 1.90 % CAPB with Total number 1 1 1 of patients with oral desquamation Toothpaste C 0.5 % SLS 1.0 % SLS 1.5 % SLS with Total number 9 16 17 of patents with oral desquamation

Claims: Cla ims 1. Use of an amphoteric surfactant in the manufacture of a composition for the prevention, inhibition and/or reduction of aphthous ulcers. 2. Use according to claim 1, characterised in that the amphoteric surfactant is a betaine. 3. Use according to claim 2, characterised in that the amphoteric surfactant is a fatty acidamidoalkylbetaine. 4. Use according to claim 1, characterised in that the composition is an oral composition. 5. Use according to claim 4, characterised in that the oral composition is a dentifrice or a mouthwash. 6. Use according to claim 4, characterised in that the oral composition is in a gel form. 7. Use according to claims 1-6 characterised in that the composition furthermore comprises Triclosan. 8. Use according to claims 1-7, characterised in that the composition furthermore comprises a zinc salt. 9. Use according to claim 7, characterised in that the composition furthermore comprises a polymer which enhances the delivery of the Triclosan.

Inventors: CUMMINS DIANE, HAMMOND KEVIN, TRAUDT MICHAEL DAVID, VAN DER OUDERAA FRANCISCUS JOH, CUMMINS, DIANE, HAMMOND, KEVIN, TRAUDT, MICHAEL, DAVID, VAN DER OUDERAA, FRANCISCUS, JOHNANNES, G.
Applicants: CUMMINS DIANE, HAMMOND KEVIN, OUDERAA FRANCISCUS JOHNANNES G, TRAUDT MICHAEL DAVID, UNILEVER NV, UNILEVER PLC, CUMMINS, DIANE, HAMMOND, KEVIN, TRAUDT, MICHAEL, DAVID, UNILEVER N.V., VAN DER OUDERAA, FRANCISCUS, JOHNANNES, G.
Application year: 1994
Main classification: A61K31
IPC codes: A61K8, A61K31, A61K33, A61Q11